Method for treating tardive dyskinesia with botulinum toxin type B

ABSTRACT

A method and composition for treating a patient suffering from a disease, disorder or condition and associated pain include the administration to the patient of a therapeutically effective amount of a neurotoxin selected from a group consisting of Botulinum toxin types A, B, C, D, E, F and G.

FIELD OF THE INVENTION

[0001] The present invention provides novel methods for treating variousdisorders and conditions, with Botulinum toxins. Importantly, thepresent invention provides methods useful in relieving pain related tomuscle activity or contracture and therefore is of advantage in thetreatment of, for example, muscle spasm such as Temporomandibular JointDisease, low back pain, myofascial pain, pain related to spasticity anddystonia, as well as sports injuries, and pain related to contracturesin arthritis.

BACKGROUND OF THE INVENTION

[0002] Heretofore, Botulinum toxins, in particular Botulinum toxin typeA, has been used in the treatment of a number of neuromuscular disordersand conditions involving muscular spasm; for example, strabismus,blepharospasm, spasmodic torticollis (cervical dystonia), oromandibulardystonia and spasmodic dysphonia (laryngeal dystonia). The toxin bindsrapidly and strongly to presynaptic cholinergic nerve terminals andinhibits the exocytosis of acetylcholine by decreasing the frequency ofacetylcholine release. This results in local paralysis and hencerelaxation of the muscle afflicted by spasm.

[0003] For one example of treating neuromuscular disorders, see U.S.Pat. No. 5,053,005 to Borodic, which suggests treating curvature of thejuvenile spine, i.e., scoliosis, with an acetylcholine releaseinhibitor, preferably Botulinum toxin A.

[0004] For the treatment of strabismus with Botulinum toxin type A, seeElston, J. S., et al., British Journal of Ophthalmology, 1985, 69,718-724 and 891-896. For the treatment of blepharospasm with Botulinumtoxin type A, see Adenis, J. P., et al., J. Fr. Ophthalmol., 1990, 13(5) at pages 259-264. For treating squint, see Elston, J. S., Eye, 1990,4(4):VII. For treating spasmodic and oromandibular dystonia torticollis,see Jankovic et al., Neurology, 1987, 37, 616-623.

[0005] Spasmodic dysphonia has been treated with Botulinum toxin type A.See Blitzer et al., Ann. Otol. Rhino. Laryngol, 1985, 94, 591-594.Lingual dystonia was treated with Botulinum toxin type A according toBrin et al., Adv. Neurol. (1987) 50, 599-608. Finally, Cohen et al.,Neurology (1987) 37 (Suppl. 1), 123-4, discloses the treatment ofwriter's cramp with Botulinum toxin type A.

[0006] The term Botulinum toxin is a generic term embracing the familyof toxins produced by the anaerobic bacterium Clostridium botulinum and,to date, seven immunologically distinct neurotoxins have beenidentified. These have been given the designations A, B, C, D, E, F andG. For further information concerning the properties of the variousBotulinum toxins, reference is made to the article by Jankovic and Brin,The New England Journal of Medicine, No. 17, 1990, pp. 1186-1194, and tothe review by Charles L. Hatheway in Chapter 1 of the book entitledBotulinum Neurotoxin and Tetanus Toxin, L. L. Simpson, Ed., published byAcademic Press Inc. of San Diego, Calif., 1989, the disclosures in whichare incorporated herein by reference.

[0007] The neurotoxic component of Botulinum toxin has a molecularweight of about 150 kilodaltons and is thought to comprise a shortpolypeptide chain of about 50 kD which is considered to be responsiblefor the toxic properties of the toxin, i.e., by interfering with theexocytosis of acetylcholine, by decreasing the frequency ofacetylcholine release, and a larger polypeptide chain of about 100 kDwhich is believed to be necessary to enable the toxin to bind to thepresynaptic membrane.

[0008] The “short” and “long” chains are linked together by means of asimple disulfide bridge. (It is noted that certain serotypes ofBotulinum toxin, e.g., type E, may exist in the form of a single chainun-nicked protein, as opposed to a dichain. The single chain form isless active but may be converted to the corresponding dichain by nickingwith a protease, e.g., trypsin. Both the single and the dichain areuseful in the method of the present invention.)

[0009] In general, four physiologic groups of C. botulinum arerecognized (I, II, III, IV). The organisms capable of producing aserologically distinct toxin may come from more than one physiologicalgroup. For example, Type B and F toxins can be produced by strains fromGroup I or II. In addition, other strains of clostridial species (C.baratii, type F; C. butyricum, type E; C. novyi, type C₁ or D) have beenidentified which can produce botulinum neurotoxins.

[0010] Immunotoxin conjugates of ricin and antibodies, which arecharacterized as having enhanced cytotoxicity through improving cellsurface affinity, are disclosed in European Patent Specification 0 129434. The inventors note that botulinum toxin may be utilized in place ofricin.

[0011] Botulinum toxin is obtained commercially by establishing andgrowing cultures of C. botulinum in a fermenter and then harvesting andpurifying the fermented mixture in accordance with known techniques.

[0012] Botulinum toxin type A, the toxin type generally utilized intreating neuromuscular conditions, is currently available commerciallyfrom several sources; for example, from Porton Products Ltd. UK, underthe trade name “DYSPORT,” and from Allergan, Inc., Irvine, Calif., underthe trade name BOTOX®.

[0013] It is one object of the invention to provide novel treatments ofneuromuscular disorders and conditions with various Botulinum toxintypes. It is another object of the present invention to relieve painwith various Botulinum toxin types.

SUMMARY OF THE INVENTION

[0014] The present invention provides a method for relieving pain,associated with muscle contractions, a composition and a method oftreating conditions such as cholinergic controlled secretions includingexcessive sweating, lacrimation and mucus secretions and a method fortreating smooth muscle disorders including, but not limited to, spasmsin the sphincter of the cardiovascular arteriole, gastrointestinalsystem, urinary, gall bladder and rectum, which method comprisesadministering to the patient suffering from said disorder or condition atherapeutically effective amount of Botulinum toxin selected from thegroup consisting of Botulinum toxin types B, C, D, E, F and G.

[0015] Each serotype of Botulinum toxin has been identified asimmunologically different proteins through the use of specificantibodies. For example, if the antibody (antitoxin) recognizes, thatis, neutralizes the biological activity of, for example, type A it willnot recognize types B,C,D, E, F or G.

[0016] While all of the Botulinum toxins appear to be zincendopeptidases, the mechanism of action of different serotypes, forexample, A and E within the neuron appear to be different than that ofType B. In addition, the neuronal surface “receptor” for the toxinappears to be different for the serotypes.

[0017] In the area of use of the Botulinum toxins in accordance with thepresent invention with regard to organ systems which involve the releaseof neurotransmitter, it is expected to introduce the toxins A, B, C, D,E, F, and G directly by local injections.

DETAILED DESCRIPTION

[0018] The Botulinum toxins used according to the present invention areBotulinum toxins type A, B, C, D, E, F and G.

[0019] The physiologic groups of Clostridium botulinum types are listedin Table I. TABLE I Physiologic Groups of Clostridium botulinumPhenotypically Toxin Glucose Phages Related Sero- Milk Fermen- &Clostridium Group Type Biochemistry Digest tation Lipase Plasmids(nontoxigenic) I A,B,F proteolytic saccharolytic + + + + C. sporogenesII B,E,F nonproteolytic saccharolytic − + + + psychotrophic III C,Dnonproteolytic saccharolytic ± + + + C. novyi IV G proteolyticnonsaccharolytic + − − − C. subterminale

[0020] These toxin types may be produced by selection from theappropriate physiologic group of Clostridium botulinum organisms. Theorganisms designated as Group I are usually referred to as proteolyticand produce Botulinum toxins of types A, B and F. The organismsdesignated as Group II are saccharolytic and produce Botulinum toxins oftypes B, E and F. The organisms designated as Group III produce onlyBotulinum toxin types C and D and are distinguished from organisms ofGroups I and II by the production of significant amounts of propionicacid. Group IV organisms only produce neurotoxin of type G. Theproduction of any and all of the Botulinum toxin types A, B, C, D, E, Fand G are described in Chapter 1 of Botulinum Neurotoxin and TetanusToxin, cited above, and/or the references cited therein. Botulinumtoxins types B, C, D, E, F and G are also available from various speciesof clostridia.

[0021] Currently fourteen species of clostridia are consideredpathogenic. Most of the pathogenic strains produce toxins which areresponsible for the various pathological signs and symptoms. Organismswhich produce Botulinum toxins have been isolated from botulismoutbreaks in humans (types A, B, E and F) and animals (types C and D).Their identities were described through the use of specific antitoxins(antibodies) developed against the earlier toxins. Type G toxin wasfound in soil and has low toxigenicity. However, it has been isolatedfrom autopsy specimens, but thus far there has not been adequateevidence that type G botulism has occurred in humans.

[0022] Preferably, the toxin is administered by means of intramuscularinjection directly into a local area such as a spastic muscle,preferably in the region of the neuromuscular junction, althoughalternative types of administration (e.g., subcutaneous injection),which can deliver the toxin directly to the affected region, may beemployed where appropriate. The toxin can be presented as a sterilepyrogen-free aqueous solution or dispersion and as a sterile powder forreconstitution into a sterile solution or dispersion.

[0023] Where desired, tonicity adjusting agents such as sodium chloride,glycerol and various sugars can be added. Stabilizers such as humanserum albumin may also be included. The formulation may be preserved bymeans of a suitable pharmaceutically acceptable preservative such as aparaben, although preferably it is unpreserved.

[0024] It is preferred that the toxin is formulated in unit dosage form;for example, it can be provided as a sterile solution in a vial or as avial or sachet containing a lyophilized powder for reconstituting asuitable vehicle such as saline for injection.

[0025] In one embodiment, the Botulinum toxin is formulated in asolution containing saline and pasteurized human serum albumin, whichstabilizes the toxin and minimizes loss through non-specific adsorption.The solution is sterile filtered (0.2 micron filter), filled intoindividual vials and then vacuum-dried to give a sterile lyophilizedpowder. In use, the powder can be reconstituted by the addition ofsterile unpreserved normal saline (sodium chloride 0.9% for injection).

[0026] The dose of toxin administered to the patient will depend uponthe severity of the condition; e.g., the number of muscle groupsrequiring treatment, the age and size of the patient and the potency ofthe toxin. The potency of the toxin is expressed as a multiple of theLD₅₀ value for the mouse, one unit (U) of toxin being defined as beingthe equivalent amount of toxin that kills 50% of a group of 18 to 20female Swiss-Webster mice, weighing about 20 grams each.

[0027] The dosages used in human therapeutic applications are roughlyproportional to the mass of muscle being injected. Typically, the doseadministered to the patient may be up from about 0.01 to about 1,000units; for example, up to about 500 units, and preferably in the rangefrom about 80 to about 460 units per patient per treatment, althoughsmaller of larger doses may be administered in appropriate circumstancessuch as up to about 50 units for the relief of pain and in controllingcholinergic secretions.

[0028] As the physicians become more familiar with the use of thisproduct, the dose may be changed. In the Botulinum toxin type A,available from Porton, DYSPORT, 1 nanogram (ng) contains 40 units. 1 ngof the Botulinum toxin type A, available from Allergan, Inc., i.e.,BOTOX®, contains 4 units. The potency of Botulinum toxin and its longduration of action mean that doses will tend to be administered on aninfrequent basis. Ultimately, however, both the quantity of toxinadministered and the frequency of its administration will be at thediscretion of the physician responsible for the treatment and will becommensurate with questions of safety and the effects produced by thetoxin.

[0029] In some circumstances, particularly in the relief of painassociated with sports injuries, such as, for example, charleyhorse,botulinum type F, having a short duration activity, is preferred.

[0030] The invention will now be illustrated by reference to thefollowing nonlimiting examples.

[0031] In each of the examples, appropriate areas of each patient areinjected with a sterile solution containing the confirmation ofBotulinum toxin. Total patient doses range from about 0.01 units to 460units. Before injecting any muscle group, careful consideration is givento the anatomy of the muscle group, the aim being to inject the areawith the highest concentration of neuromuscular junctions, if known.Before injecting the muscle, the position of the needle in the muscle isconfirmed by putting the muscle through its range of motion andobserving the resultant motion of the needle end. General anaesthesia,local anaesthesia and sedation are used according to the age of thepatient, the number of sites to be injected, and the particular needs ofthe patient. More than one injection and/or sites of injection may benecessary to achieve the desired result. Also, some injections,depending on the muscle to be injected, may require the use of fine,hollow, teflon-coated needles, guided by electromyography.

[0032] Following injection, it is noted that there are no systemic orlocal side effects and none of the patients are found to developextensive local hypotonicity. The majority of patients show animprovement in function both subjectively and when measured objectively.

EXAMPLE 1 The Use of Botulinum Toxin Type in the Treatment of TardiveDyskinesia

[0033] A male patient, age 45, suffering from tardive dyskinesiaresulting from the treatment with an antipsychotic drug, such asThorazine or Haldol, is treated with 150 units of Botulinum toxin type Bby direct injection of such toxin into the facial muscles. After 1-3days, the symptoms of tardive dyskinesia, i.e., orofacial dyskinesia,athetosis, dystonia, chorea, tics and facial grimacing, etc. aremarkedly reduced.

EXAMPLE 1(a)

[0034] The method of Example 1 is repeated, except that a patientsuffering from tardive dyskinesia is injected with 50-200 units ofBotulinum toxin type C. A similar result is obtained.

EXAMPLE 1(b)

[0035] The method of Example 1 is repeated, except that a patientsuffering from tardive dyskinesia is injected with 50-200 units ofBotulinum toxin type D. A similar result is obtained.

EXAMPLE 1(c)

[0036] The method of Example 1 is repeated, except that a patientsuffering from tardive dyskinesia is injected with 50-200 units ofBotulinum toxin type E. A similar result is obtained.

EXAMPLE 1(d)

[0037] The method of Example 1 is repeated, except that a patientsuffering from tardive dyskinesia is injected with 50-200 units ofBotulinum toxin type F. A similar result is obtained.

EXAMPLE 1(e)

[0038] The method of Example 1 is repeated, except that a patientsuffering from tardive dyskinesia is injected with 50-200 units ofBotulinum toxin type G. A similar result is obtained.

EXAMPLE 2 The Use of Botulinum Toxin Type B in the Treatment ofSpasmodic Torticollis

[0039] A male, age 45, suffering from spasmodic torticollis, asmanifested by spasmodic or tonic contractions of the neck musculature,producing stereotyped abnormal deviations of the head, the chin beingrotated to one side, and the shoulder being elevated toward the side atwhich the head is rotated, is treated by injection with 100-1,000 unitsof Botulinum toxin type E. After 3-7 days, the symptoms aresubstantially alleviated; i.e., the patient is able to hold his head andshoulder in a normal position.

EXAMPLE 2(a)

[0040] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type B. A similar result is obtained.

EXAMPLE 2(b)

[0041] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type C. A similar result is obtained.

EXAMPLE 2(c)

[0042] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type D. A similar result is obtained.

EXAMPLE 2(d)

[0043] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type E. A similar result is obtained.

EXAMPLE 2(e)

[0044] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type F. A similar result is obtained.

EXAMPLE 2(f)

[0045] The method of Example 2 is repeated, except that a patientsuffering from spasmodic torticollis is injected with 100-1,000 units ofBotulinum toxin type G. A similar result is obtained.

EXAMPLE 3 The Use of Botulinum Toxin in the Treatment of EssentialTremor

[0046] A male, age 45, suffering from essential tremor, which ismanifested as a rhythmical oscillation of head or hand muscles and isprovoked by maintenance of posture or movement, is treated by injectionwith 50-1,000 units of Botulinum toxin type B. After two to eight weeks,the symptoms are substantially alleviated; i.e., the patient's head orhand ceases to oscillate.

EXAMPLE 3(a)

[0047] The method of Example 3 is repeated, except that a patientsuffering from essential tremor is injected with 100-1,000 units ofBotulinum toxin type C. A similar result is obtained.

Example 3(b)

[0048] The method of Example 3 is repeated, except that a patientsuffering from essential tremor is injected with 100-1,000 units ofBotulinum toxin type D. A similar result is obtained.

EXAMPLE 3(c)

[0049] The method of Example 3 is repeated, except that a patientsuffering from essential tremor is injected with 100-1,000 units ofBotulinum toxin type E. A similar result is obtained.

EXAMPLE 3(d)

[0050] The method of Example 3 is repeated, except that a patientsuffering from essential tremor is injected with 100-1,000 units ofBotulinum toxin type F. A similar result is obtained.

EXAMPLE 3(e)

[0051] The method of Example 3 is repeated, except that a patientsuffering from essential tremor is injected with 100-1,000 units ofBotulinum toxin type G. A similar result is obtained.

EXAMPLE 4 The Use of Botulinum Toxin in the Treatment of SpasmodicDysphonia

[0052] A male, age 45, unable to speak clearly, due to spasm of thevocal chords, is treated by injection of the vocal chords with Botulinumtoxin type B, having an activity of 80-500 units. After 3-7 days, thepatient is able to speak clearly.

EXAMPLE 4(a)

[0053] The method of Example 4 is repeated, except that a patientsuffering from spasmodic dysphonia is injected with 80-500 units ofBotulinum toxin type C. A similar result is obtained.

EXAMPLE 4(b)

[0054] The method of Example 4 is repeated, except that a patientsuffering from spasmodic dysphonia is injected with 80-500 units ofBotulinum toxin type D. A similar result is obtained.

EXAMPLE 4(c)

[0055] The method of Example 4 is repeated, except that a patientsuffering from spasmodic dysphonia is injected with 80-500 units ofBotulinum toxin type E. A similar result is obtained.

EXAMPLE 4(d)

[0056] The method of Example 4 is repeated, except that a patientsuffering from spasmodic dysphonia is injected with 80-500 units ofBotulinum toxin type F. A similar result is obtained.

EXAMPLE 4(e)

[0057] The method of Example 4 is repeated, except that a patientsuffering from spasmodic dysphonia is injected with 8-500 units ofBotulinum toxin type G. A similar result is obtained.

EXAMPLE 5 The Use of Botulinum Toxin Types A-G in the Treatment ofExcessive Sweating, Lacrimation or Mucus Secretion or Other CholinergicControlled Secretions

[0058] A male, age 65, with excessive unilateral sweating is treated byadministering 0.01 to 50 units, of Botulinum toxin, depending upondegree of desired effect. The larger the dose, usually the greaterspread and duration of effect. Small doses are used initially. Anyserotype toxin alone or in combination could be used in this indication.The administration is to the gland nerve plexus, ganglion, spinal cordor central nervous system to be determined by the physician's knowledgeof the anatomy and physiology of the target glands and secretary cells.In addition, the appropriate spinal cord level or brain area can beinjected with the toxin (although this would cause many effects,including general weakness). Thus, the gland (if accessible) or thenerve plexus or ganglion are the targets of choice. Excessive sweating,tearing (lacrimation), mucus secretion or gastrointestinal secretionsare positively influenced by the cholinergic nervous system. Sweatingand tearing are under greater cholinergic control than mucus or gastricsecretion and would respond better to toxin treatment. However, mucusand gastric secretions could be modulated through the cholinergicsystem. All symptoms would be reduced or eliminated with toxin therapyin about 1-7 days. Duration would be weeks to several months.

EXAMPLE 6 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms in Smooth Muscle Disorders such as Sphincters of theCardiovascular Arteriole, Gastrointestinal System, Urinary or GallBladder, Rectal, Etc.

[0059] A male, age 30-40, with a constricted pyloric valve whichprevents his stomach from emptying, is treated by administering 1-50units of Botulinum toxin. The administration is to the pyloric valve(which controls release of stomach contents into the intestine) dividedinto 2 to 4 quadrants, injections made with any endoscopic device orduring surgery. In about 1-7 days, normal emptying of the stomach,elimination or drastic reduction in regurgitation occurs.

EXAMPLE 7 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inTemporal Mandibular Joint Disorders

[0060] A female, age 35, is treated by administration of 0.1 to 50 unitstotal of Botulinum toxin. The administration is to the musclescontrolling the closure of the jaw. Overactive muscles may be identifiedwith EMG (electromyography) guidance. Relief of pain associated withmuscle spasms, possible reduction in jaw clenching occurs in about 1-3days.

EXAMPLE 8 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inConditions Secondary to Sports Injuries (Charleyhorse)

[0061] A male, age 20, with severe cramping in thigh after sports injuryis treated by administration of a short duration toxin, possible lowdose (0.1-25 units) of preferably type F to the muscle and neighboringmuscles which are in contraction (“cramped”). Relief of pain occurs in1-7 days.

EXAMPLE 9 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inSmooth Muscle Disorders Such as Gastrointestinal Muscles

[0062] A female, age 35, with spastic colitis, is treated with 1-100units of Botulinum toxin divided into several areas, enema (1-5 units)delivered in the standard enema volume, titrate dose, starting with thelowest dose. Injection is to the rectum or lower colon or a low doseenema may be employed. Cramps and pain associated with spastic colon arerelieved in 1-10 days.

EXAMPLE 9 The Use of Botulinum Toxin Types A-G in the Treatment ofMuscle Spasms and Control of Pain Associated with Muscle Spasms inSpasticity Conditions Secondary to Stroke, Traumatic Brain or SpinalCord Injury

[0063] A male, age 70, post-stroke or cerebral vascular event, isinjected with 50 to 300 units of Botulinum toxin in the major musclesinvolved in severe closing of hand and curling of wrist and forearm orthe muscles involved in the closing of the legs such that the patientand attendant have difficulty with hygiene. Relief of these symptomsoccurs in 7 to 21 days.

EXAMPLE 10 The Use of Botulinum Toxin Types A-G in the Treatment ofPatients with Swallowing Disorders

[0064] A patient with a swallowing disorder caused by excessive throatmuscle spasms is injected with about 1 to about 300 units of Botulinumtoxin in the throat muscles. Relief the swallowing disorder occurs inabout 7 to about 21 days.

EXAMPLE 11 The Use of Botulinum Toxin Types A-G in the Treatment ofPatients with Tension Headache

[0065] A patient with a tension headache caused by excessive throatmuscle spasms is injected with about 1 to about 300 units of Botulinumtoxin in muscles of the head and upper neck. Relief the tension headacheoccurs in about 1 to about 7 days.

[0066] Although there has been hereinabove described a use of Botulinumtoxins for treating various disorders, conditions and pain, inaccordance with the present invention, for the purpose of illustratingthe manner in which the invention may be used to advantage, it should beappreciated that the invention is not limited thereto since many obviousmodifications can be made, and it is intended to include within thisinvention any such modifications as will fall within the scope of theappended claims. Accordingly, any and all modifications, variations, orequivalent arrangements which may occur to those skilled in the art,should be considered to be within the scope of the present invention asdefined in the appended claims.

What is claimed is:
 1. A method of treating cholinergic controlledsecretions including excessive sweating, lacrimation and mucussecretion, said method comprising administering to the patient atherapeutically effective amount of Botulinum toxin type A in order toreduce the secretion.
 2. The method according to claim 1 wherein theBotulinum toxin type A is administered to the patient's nerve plexus inan amount of between about 0.01 and about 50 units.
 3. The methodaccording to claim 1 wherein the Botulinum toxin type A is administeredto the patient's ganglion in an amount of between about 0.01 and about50 units.
 4. The method according to claim 1 wherein the Botulinum toxintype A is administered to the patient's spinal cord in an amount ofbetween about 0.01 and about 50 units.
 5. The method according to claim1 wherein the Botulinum toxin type A is administered to the patient'scentral nervous system in an amount of between about 0.01 and about 50units.
 6. A method for relieving pain associated with smooth muscledisorders, including spasms in the sphincters of the cardiovasculararteriole, gastrointestinal system, urinary, gall bladder and rectum,said method comprising administering to the patient a therapeuticallyeffective amount of Botulinum toxin type A in order to relieve pain. 7.The method according to claim 6 wherein the Botulinum toxin type A isadministered to the patient's pyloric valve in an amount between about 1and about 50 units.
 8. A method for treating smooth muscle disorders,including spasms in the sphincters of the cardiovascular arteriole,gastrointestinal system, urinary, gall bladder and rectum, said methodcomprising administering to the patient a therapeutically effectiveamount of Botulinum toxin type A in order to lessen the spasms.
 9. Themethod according to claim 8 wherein the Botulinum toxin type A isadministered to the patient's pyloric valve in an amount between about 1and about 50 units.
 10. A method for relieving pain associated withsmooth muscle disorders, including spasms in the lower gastrointestinalmuscles and rectum, said method comprising administering to the patienta therapeutically effective amount of Botulinum toxin type A in order torelieve pain.
 11. The method according to claim 10 wherein the Botulinumtoxin type A is administered to the patient's lower colon in an amountbetween about 0.01 and about 50 units.
 12. A method for relieving painassociated with smooth muscle disorders, including spasms in thesphincters lower gastrointestinal muscles and rectum, said methodcomprising administering to the patient a therapeutically effectiveamount of Botulinum toxin type A in order to lessen the spasms.
 13. Themethod according to claim 12 wherein the Botulinum toxin type A isadministered to the patient's lower colon in an amount between about0.01 and about 50 units.
 14. A method for relieving pain associated withmuscle spasms in conditions secondary to sports injuries, said methodcomprising administering to a patient a therapeutically effective amountof a Botulinum toxin of a type having short duration activity in orderto relieve pain.
 15. The method according to claim 14 wherein theBotulinum toxin comprises Botulinum toxin type F.
 16. The methodaccording to claim 15 wherein the therapeutic amount comprises a dose ofbetween about 1 and about 10 units.
 17. The method according to claim 16wherein the muscle spasms occur in a patient's thigh and the Botulinumtoxin is administered into the thigh
 18. A method for relieving painassociated with contractions in arthritis, said method comprisingadministering to a patient a therapeutically effective amount of aBotulinum toxin in order to relieve pain.
 19. A method for treatingswallowing disorders, including spasms, said method comprisingadministering to the patient a therapeutically effective amount ofBotulinum toxin type A.
 20. A method for treating tension headachecomprising administering to the patient a therapeutically effectiveamount of Botulinum toxin type A.